Extramuscular treatment of traumatic-induced migraine headache

ABSTRACT

A method for selection and treatment of externally caused migraine headache, the method includes identifying a patient group having chronic migraine headache; determining the identified patient group, a specific patient with a post traumatic migraine headache; and administering to the selected patient by injection of a therapeutically effective amount of an invertebrate presynaptic neurotoxin in a pharmaceutically safe form to the selected patient&#39;s head or upper neck; administration preferably being on the sites of the trigeminal cervical system, enabling axonal transport of the neurotoxin from distal to central sites; and the administration preferably comprising extramuscular injection of the neurotoxin of suitable dilution (a) over the aponeurotic fascia to enable the neurotoxin to diffuse into distal sensory nerves, in order to concentrate the neurotoxin over the occipital-parietal-frontal head region, or (b) intra-orally, in a foramina of the sphenopalatine ganglion for enabling diffusion of the neurotoxin to the ganglion, or (c) to emerging exit points of nerves including foraminal sites for enabling the neurotoxin access to concentrated nerve bundles at exit points of the foramina.

Trauma has been documented to increase frequency of migraine headacheand is a risk factor for conversion from episodic to chronic migraine.

Anxiety and depression are more often associated with chronic migrainethan episodic migraine, while trauma may be implicated in initiating orworsening migraine. There are a number of different trauma modalitiesthat can be involved in this process such as:

-   1. Closed head injury, this includes blast injuries-   2. Open head injury, with intra-parenchymal lesions such as    hematomas and contusions-   3. Post craniotomy with trauma secondary to surgical effects as well    as the underlying condition-   4. Psychological trauma, such as depression, anxiety, post traumatic    syndrome and post-traumatic stress disorder (PTSD)-   5. Whiplash injury as well as other soft tissue injuries around the    head and neck area

The International Headache Society classifies post-traumatic headacheand migraine separately. The post-traumatic headache requires that theheadache start within one week of the trauma. If the headache persistsfor less than 3 months after this it is referred to as an AcutePost-Traumatic headache. If the headache persists for longer than 3months it is referred to as a Chronic Post-Traumatic headache. Theseheadaches are further sub-divided into mild, moderate or severedepending on the extent of the injury that caused the headache. Inaddition there is a category for headaches attributed to whiplashinjury. The actual features of the post-traumatic headache are notdescribed in the classification but these can resemble migrainefeatures. Furthermore episodic migraine can transform to chronicmigraine as a result of head trauma. In these cases there is a priorhistory of migraine, which increases in frequency after the trauma.

Botulinum toxins have been used to treat migraine headache. This is wellestablished in the art. By way of example only, see U.S. Pat. No.5,714,468, U.S. Pat. No. 5,721,215, U.S. Pat. No. 6,458,365, U.S. Pat.No. 7,655,244, U.S. Pat. No. 7,704,511, and U.S. Pat. No. 7,981,433. Allof these references are to be incorporated herewith in their entirety.These patents include: Binder; Botulinum toxin injections to the headfor migraine, Blumenfeld; Botulinum toxin injections to thesphenopalatine ganglion, nasal approach and vascular approach, sutureline technique (these are not foramina or exit points); Aoki; Tensiontype headache treatment with Botulinum toxin, and Turkel; 31 sites asfor the FDA approved protocol for chronic migraine.

Heretofore, onabotulinumtoxinA has been FDA approved for chronicmigraine, and the dose used is 155 to 195 units, with a dilution of 2 ccper 100 units of onabotulinumtoxinA. Doses ranging from 25 units to 260units have been used to treat various headache disorders. These haveinvolved intra-muscular injections in fixed sites and follow the painsites.

Botulinum toxin side effects are usually due to local diffusion tosurrounding muscles producing unwanted weakness.

SUMMARY OF THE INVENTION

The method in accordance with the present invention for selection andtreatment of externally caused migraine headache generally includesidentifying a patient group having migraine headache, and of theidentified patient group, determining a specific patient with a posttraumatic migraine headache. Thereafter, the selected patient isadministered with a therapeutically effective amount of an invertebratepresynaptic neurotoxin in a pharmaceutically safe form to the selectedpatient's head.

The present invention is also directed to treating post-traumaticmigraine headaches with Botulinum toxin (and/or endopeptidase) byadjusting the toxin concentration and volume to establish optimumdiffusion of toxin in non-muscle related areas of the head and neck,such as fascia injections to the scalp or exit points of nerves in themouth and neck. The improvement avoids side effects such as muscleparalysis and reduces doses overall, e.g., use of high concentration/lowvolume injections at nerve exit points and low concentration/high volumeinjections in fascia on the scalp.

The present invention includes but is not limited to closed head injury,including blast injuries; open head injury, with intra-parenchymallesions such as hematomas and contusions, post craniotomy with traumasecondary to surgical effects; psychological trauma, such as depression,anxiety, and post-traumatic stress disorder; and whiplash injury as wellas other soft tissue injuries around the head and neck area

The preferred method in accordance with the present invention forselection and treatment of externally caused migraine headache generallyincludes identifying a patient group having migraine headache, and ofthe identified patient group, determining a specific patient with a posttraumatic migraine headache. Thereafter, the selected patient isadministered with a therapeutically effective amount of an invertebratepresynaptic neurotoxin in a pharmaceutically safe form to non-musclerelated areas of the selected patient's head and neck. In many of theseselected post-traumatic headache patients, unwanted side effects ofmuscle weakness associated with the use of Botulinum toxins cannot betolerated.

In general, a method for treating a patient with migraine headache inaccordance with the present invention includes administering to thepatient a therapeutically effective amount of an invertebratepresynaptic neurotoxin in a pharmaceutically safe form.

The administration advantageously includes extramuscular injection ofthe neurotoxin of suitable dilution (a) over the aponeurotic fascia toenable the neurotoxin to diffuse into distal sensory nerves, in order toconcentrate the neurotoxin over the occipital-parietal-frontal headregion, or (b) intra-orally, in a foramina of the sphenopalatineganglion for enabling diffusion of the neurotoxin to the ganglion, or(c) to emerging exit points of nerves including foraminal sites forenabling more concentrated dilution of the neurotoxin access toconcentrated nerve bundles at exit points of the foramina.

The invention further includes the following methods:

The method wherein the neurotoxin is delivered to the face, cranium, andneck.

The method wherein externally caused migraine headache is post-traumaticstress disorder (PTSD). The method wherein externally caused migraineheadache is traumatic brain injury (TBI).

The method wherein the presynaptic neurotoxin is a Botulinum toxin.

The method where the Botulinum toxin is Botulinum toxin A.

The method wherein the neurotoxin comprises an Endotoxin.

The method wherein the Endotoxin is an endopeptidase derived frombotulinum toxin.

In general, the present invention aims to minimize the side effectspresent with prior injection techniques and uses a novel injectionapproach to achieve this goal. In addition, this invention aims toincrease the efficacy across multiple headache types including chronicand episodic migraine, post-traumatic headache, post-craniotomyheadache, tension type headache and medication overuse headache. Thisinvention focuses the medication on the sites of maximal benefit; i.e.,the trigemino-cervical nerves and the sphenopalatine ganglion nerves.

The technique involves administration to allow for maximizing the doseand thus the effect on the trigeminal cervical system and sphenopalatineganglion system; while minimizing the side effects.

This invention uses the same methods of administration described in theprocedures above to deliver endotoxins to the same sites. Endotoxins donot cause muscle weakness as they are targeted to sensory nerves,however the current technique of intra-muscular injections can stillcause side effects related to needle trauma to muscle and the need toperform multiple injections.

More specifically, the administration includes the extramuscularinjection of diluted Botulinum toxin.

Still more particularly, the method the Botulinum toxins may beBotulinum Toxin A, B, C, D, E, F, and G.

BRIEF DESCRIPTION OF THE DRAWINGS

The advantages and features of the present invention will be betterunderstood by the following description when considered in conjunctionwith the accompanying drawings, in which:

FIG. 1 is a diagram of injection sites in accordance with the presentinvention showing the frontal (10), parietal (20), and occipital (30)aponeurotic fascia in head 14;

FIG. 2 is a diagram of injection sites in accordance with the presentinvention; and refers specifically tot eh greater and lesser palatineforamen (20) which are nerve exit points for the palatine nerve and theincisive foramen (30) a nerve exit point for the nasopalatine nerve; and

FIG. 3 illustrates suitable nerve exit points in the head and neck.

DETAILED DESCRIPTION

It has been reported that nearly forty-percent (40%) of soldiers hadmigraines or probable migraines during their tours of duty, but few hada history of migraines before their deployments. In accordance with thepresent invention, a patient group can be identified by survey. Forexample, nineteen percent (19%) of the 2,687 soldiers surveyed uponreturn from duty met the criteria for definite migraines, eighteenpercent (18%) had probable migraines, and eleven percent (11%)non-migraine-type headaches. Those with definite migraines had anaverage of 3.5 migraine days/month.

Just five percent (5%) of the soldiers had a history of migraineheadaches prior to their deployments to Iraq.

As an example, after returning home from Iraq, soldiers are sent througha medical processing site. Members of one brigade completed a validated17-question survey about headaches. Based on their survey responses,soldiers were divided into three groups: definite migraines, probablemigraines, or non-migraine headaches, a system of classification similarto that used in the American Migraine Study.

The mean age of respondents was 27. The group was ninety-five percent(95%) male and five-percent (5%) female.

Soldiers rated their migraine headaches as a mean 6.5 on a 10-pointseverity scale, lasting an average of 5.2 hours. Yet only 2% receivedtriptans, the standard of care for the treatment of acute migraines.

Findings from a 3-month follow-up survey indicate that many soldierscontinue to have elevated rates of migraines after their returnstateside.

After identification of an identified patient group, continued surveycan be used to determine specific patients with post-traumatic migraineheadache and thereafter the selected patient is administered atherapeutically effective amount of an invertebrate presynapticneurotoxin in a pharmaceutically safe form specifically to non-musclerelated areas of the patients head.

Current injection techniques known in the art today use a system offlooding the potential structures involved with migraine pathogenesiswith the medication, but this may lead to unwanted side effects. Thisinvention avoids this by with the most efficiency by targeting the sitesof most benefit, i.e., see FIGS. 1-3, with the most efficiency. Thetechnique also utilizes adjustments in concentrations to establishdiffusion of medication in non-muscle related areas. Unlike theBlumenfeld patent for the use of Botulinum toxin to treat migraine witha spenopalatine ganglion approach, this invention uses a much moresuperficial and less painful approach to reach this target than theintra-nasal technique recommended in that patent.

Importantly, the present invention utilizes the proximal axonaltransport of Botulinum toxins from distal to central sites.

The technique, in accordance with the present invention involves 3different modalities of administration to allow for maximizing the doseand thus the effect on the trigeminal cervical system and sphenopalatineganglion system; while minimizing the side effects.

Injection Modalities:

1. Dilute Botulinum toxin: about 4-10 cc per 100 units is injected overthe aponeurotic fascia, not into muscle, allowing the toxin to diffuseinto distal sensory nerve endings that are concentrated over theoccipital-parietal-frontal head regions. (There is no muscle in thislocation). No muscle weakness results as all the injections are innon-muscular regions. The toxin diffuses in a broad area due to thedilution; allowing for a decrease in the number of injection sites.Botulinum toxin is delivered to the distal sensory nerve ending in thescalp. See FIG. 1.2. Intra-oral injections are done in the region of the foramina of thesphenopalatine ganglion, this allows diffusion of toxin to the ganglionwithout a deep injection through muscle. Thus, lower doses can be used.There is no risk of muscle trauma including intra-muscular hemorrhagerelated to needles tracking through muscle to reach the sphenopalatineganglion. The dilution for these injections is about 1 cc per 100 unitsof Botulinum toxin, to prevent diffusion to other intraoral structures.See FIG. 2.

3. Emerging nerve points which include foraminal injection sites andforaminal injection sites deep to the muscle layer allows Botulinumtoxin access to the concentrated nerve bundles at the exit points andthus lower doses with improved efficacy and less side effects andadverse events can be achieved. The cervical plexus emerges from theposterior portion of the sternomastoid muscle and injections at thissite can encompass the entire distribution of the cervical plexus. Thedilution for these injections is about 1 cc per 100 units of Botulinumtoxin. The concentrated solution prevents diffusion to local muscle andthe accurate needle placement allows the medication to be delivered tothe site where it will most effective. See FIG. 3.

With reference to FIG. 3, sensory branches of the trigeminal-nerves(ophthalmic V1, maxillary V2 and mandibular V3) leave the skull throughthree separate foramina; in the following order: the superior orbitalfissure, the foramen rotundum, and the foramen ovale.

V1 carries information from the scalp (forehead to vertex) upper eyelidand eye, nose and nasal mucosa, meninges and frontal sinuses.

V2 carries information from lower eyelid, cheek, upper lip, dentition,mouth meninges and sinuses (ethmoid and sphenoid).

V3 carries information from lower lip, dentition, jaw, external ear,meninges.

Note all 3 divisions supply the meninges.

By way of illustration, injections are made at sites 10 on a scalp 14 oneach side of the aponeurotic fascia 18 with a 4-10 cc dilution allowingfor a broad diffusion of the Botulinum toxin, see FIG. 1. However, forthe forminal and emerging nerve bundle injections a 1 cc dilution isused to prevent diffusion to surrounding muscles, see FIGS. 2 and 3.

The foraminal anatomy is as follows:

Frontal region—supraorbital foramen—supra-orbital nerve

-   -   Supratrochlear foramen—supratrochlear nerve

Maxilla—incisive foramen—nasopalatine nerve (Septum)

Palatine—greater and lesser palatine foramen—greater and lesser palatinenerves

Maxilla—Inferior orbital fissure/foramen—zygomatic and infra-orbitalnerves and orbital branch of the pterygopalatine ganglion (SPG).

There are two possible intra-oral approaches to the Sphenopalatineganglion. See FIG. 2. The first intra-oral method involves needleinsertion in the region of the mucobuccal fold (not shown) at themaxillary second molar and advancing the needle in a posterior,superior, and medical direction, into the region of the pterygopalatinefossa. The second intra-oral approach to the Sphenopalatine ganglion 20is through the greater palatine canal. The opening of this is locatedbetween the middle of the second molar and the middle of the thirdmolar. This site will be approximately 7 mm from the end of the hardpalate.

Clinical Examples: Case 1

18 year old male returns from Iraq where he sustains a blast closed headinjury and since that time has daily headaches that have featuressuggestive of migraine headache. He fails to respond to tricyclicantidepressants and biofeedback courses. Onabotulinum toxin is injectedusing the FDA approved protocol for onabotuliumtoxinA. He tolerates theprocedure well. He has no side effects. After 10 weeks he reports nofurther headaches.

Case 2

22 year old male returns from Iraq where he sustains a blast closed headinjury and since that time has daily headaches that have featuressuggestive of migraine headache. He fails to respond to tricyclicantidepressants and biofeedback courses. He meets criteria for chronicmigraine complicated by medication overuse headache. He also fails torespond to numerous preventive medications such as Topiramate andPropranolol. He is treated with onabotulinumtoxinA using the PREEMPTinjection protocol with fixed sites and follow-the-pain injections.Total dose given 195 units. He develops neck pain, brow ptosis and showsno improvement in headache frequency after three (3) treatment cycles.

He is then treated with the variable concentration focused injectionprotocol as outlined in this invention.

OnabotulinumtoxinA is diluted as follows: 100 units in 8 cc of normalsaline (0.1 ml contains 1.25 units) and 100 units in 1 cc of normalsaline (0.1 ml contains 10 units).

Injection sites and dosing as Follows:

8 cc Dilution

-   Frontal aponeurotic fascia 5 units each side-   Parietal aponeuotic fascia 5 units each side-   Occipital-aponeurotic 5 units each side-   Sub-total 30 units

1 cc Dilution

-   Orbital ridge supro-medial angle over supra-trochlear and    supra-orbital nerves 5 units each side-   Infraorbital foramen 5 units each side-   Mental foramen 5 units each side-   Posterior aspect, mid-section of stemocleidomastoid muscle 5 units    each side-   Occipital foramen 5 units each side-   Auriculotemporal nerve just anterior and inferior to-the tragus 5    units each side-   Intra-oral muscosal injection superior to second molar intra-oral 5    units each side-   Sub-total 60 units-   Total dose given 100 units.

Lower dosing of onabotulinumtoxinA is used as the medication isdelivered in a focus where it will have the most benefit; i.e.: nounnecessary flooding of medication to unwanted sites. 20 injections aredone instead of the more conventional 39. None of these sites match theapproved PREEMPT injection protocol for migraine. He tolerates theprocedure well. He has no side effects. The patient does not developneck weakness or pain as the neck musculature is not injected. Thepatient does not develop brow ptosis as the frontalis muscle is notinjected. After 10 weeks he reports no further headaches.

Case 3

19 year old male, returns from Iraq with a history of migraine headachespresent on 4 days out of each week. He was in Iraq for over a year, butduring this time he did not sustain any injuries in particular no headinjury. Prior to deployment he did not suffer with headaches. Hiscurrent headaches are generalized, throbbing in nature, associated withnausea and photo-phobia. They interfere with his ability to work. He isassessed as having chronic migraine triggered by stress relating to hisdeployment. He is successfully treated with onabotulinumtoxinA inaccordance with the injection methodology set forth in Case 1.

Case 4

28 year old woman is involved in a motor vehicle accident with blunthead trauma that results in an acute left epidural hematoma. Sheundergoes urgent craniotomy. The hematoma is evacuated via a leftprieto-temporal craniotomy. She gradually recovers but her course iscomplicated by ongoing headaches overt the left hemicranium. These arethrobbing in nature, interfere with her activities, and associated withnausea and vomiting. These headaches are present on a near daily basis.She is successfully treated treated with onabotulinumtoxinA inaccordance with the injection methodology as outlined in case 1 above.

The present invention may suitably comprise, consist of, or consistessentially of the recited elements. Further, the inventionillustratively disclosed herein suitably may be practiced in the absenceof any element which is not specifically disclosed herein. Accordingly,any and all modifications, variations or equivalent arrangements whichmay occur to those skilled in the art, should be considered to be withinthe scope of the present invention as defined in the appended claims.

1. A method for selection and treatment of externally caused migraineheadache, said method comprising: identifying a patient grouphaving-migraine headaches; of the identified patient group, determininga specific patient with a post traumatic chronic migraine headache; andadministering a therapeutically effective amount of an a suitablydiluted Botulinum toxin in a pharmaceutically safe form to the selectedpatient's head to reduce chronic migraine headaches.
 2. The methodaccording to claim 1 wherein the externally caused chronic migraineheadache is post-traumatic stress disorder (PTSD).
 3. The methodaccording to claim 1 wherein the externally caused chronic migraineheadache is traumatic brain injury (TBI).
 4. (canceled)
 5. The methodaccording to claim 34 wherein the Botulinum toxin is Botulinum toxin A.6. The method according to claim 34 wherein the Botulinum toxin isBotulinum Toxin B.
 7. The method according to claim 1 wherein theBotulinum toxin is an Endotoxin.
 8. The method of claim 7 wherein theEndotoxin is an endopeptidase.
 9. The method according to claim 5wherein the Botulium toxin A is onabotulinumtoxinA. 10-20. (canceled)